Steroid esters preparation

ABSTRACT

This invention relates to an improved steroid ester synthesis in which a carbodiimide, in combination with an acid catalyst, is used as condensing agent.

This invention relates to an improved steroid ester synthesis in which acarbodiimide, in combination with an acid catalyst, is used ascondensing agent for the reaction between the steroid alcohol and theesterifying agent.

BACKGROUND OF THE INVENTION

There are numerous procedures available for the preparation ofcarboxylic esters from acid and hydroxyl components. However, themethods generally involve activation of either the acid (e.g. in theform of acyl halide) or the hydroxyl (e.g. as ester) component, whichmeans introduction of an extra reaction step.

In the following, references to the literature are given by numberswithin brackets. The numbers refer to literature sources listed afterthe examples.

During recent years carbodiimides, and especially N,N¹-dicyclohexylcarbodiimide (in the following abbreviated as DCC), haveattracted increasing attention as condensing agents in ester synthesis(1, 2). Since both the acid and the hydroxyl compound are used as suchin the reaction this synthesis has the obvious advantage of proceedingwithout the extra activation step of at least one reactant.

Esters of carboxylic acids with primary or secondary alcohols, as wellas with phenols, are obtainable with this method (3). Tertiary alcoholsgenerally react in only very low yield (3). However, the yield of esteris usually decreased by the simultaneous formation of an N-acylureaderivative as by-product, as illustrated below (4, 5). ##STR1##

This by-product may also cause problems in the work-up procedure andcontaminate the desired ester. Numerous attempts have been made toincrease the yield of ester by choosing reaction conditions so as toavoid the formation of the by-product. It has been found that the use ofpyridine as solvent promotes the formation of ester (1, 6), although theappearance of smaller or larger quantities of N-acylurea usually cannotbe avoided.

It has now, surprisingly, been found that addition of a strong acid tothe pyridine solution considerably increases the yield of ester anddecreases, or even prevents, the formation of the N-acylurea compound,and that the strong acid can be used in a catalytic amount. Table 1shows that condensation of carboxylic acids with phenol and primary andsecondary alcohols in pyridine with DCC in the presence of a catalyticamount of p-toluenesulfonic acid (in the following abbreviated as pTSA)gives excellent yields of ester, whereas reaction without said catalystgives a much poorer result, due to the formation of the correspondingN-acylurea derivative.

As is seen in Table 1, the yield of ester is not particularlyoutstanding when tertiary alcohols are employed, even with pTSA added tothe reaction mixture. However, the promoting effect of the acid catalyston the ester formation is definitely evident even in this case.

Although the exact mechanism involved in the reaction is not fullyunderstood, the fact that increased yields and purity of desiredcarboxylic acid esters are realized by the addition of the strong acidinto the basic reaction mixture is indeed unexpected as, in fact, theaddition of strong acid into the present basic esterification reactionmixture is not indicated by any known prior art for any purpose. Intheory, the desirable result occurs due to suppression of sidereactions, which is most likely due in some way or other to the presenceof a salt between the pyridine and the strong acid, although once againthe way in which this salt operates to suppress the undesired sidereactions is not presently clear.

As is seen from Table 1, carboxylic esters are obtained in high yieldsfrom phenols and from primary and secondary alcohols when approximately

                  Table 1                                                         ______________________________________                                        Reaction of a carboxylic acid, a hydroxyl compound, and DCC                   (molar ratio 1.0: 1.1: 1.2) in pyridine.                                      (See examples 1 and 2 for experimental details.)                              ______________________________________                                         ##STR2##                                                                              yield (%).sup.+                                                      R          with pTSA     without pTSA                                         ______________________________________                                        n-hexyl    95            40                                                   i-propyl   98             5                                                   t-butyl     8             0                                                   phenyl     96            20                                                   ______________________________________                                         ##STR3##                                                                      ##STR4##                                                                              yield (%).sup.+                                                      R.sup.2    with pTSA     without pTSA                                         ______________________________________                                        n-butyl    96            66                                                   i-propyl   99            58                                                   t-butyl    17             3                                                   phenyl     93            39                                                   ______________________________________                                         .sup.+ Several esterifications of benzoic acid using DCC as condensing        agent are mentioned in the literature. Without any catalyst present methy     benzoate has been prepared in a 60% yield using a large excess of methano     (4), and phenyl benzoate has been obtained in a 12% yield from equimolar      amounts of reactants (7).                                                

                                      TABLE 2                                     __________________________________________________________________________    Yield of steroid esters of carboxylic acids.                                  (See Examples 3, 4, and 5 for experimental details.)                                                        yield (%).sup.+                                 ester                         with pTSA                                                                           without pTSA                              __________________________________________________________________________     ##STR5##                     85    74                                         ##STR6##                     87    50                                         ##STR7##                     89    73                                        __________________________________________________________________________     .sup. + Calculated as pure compound   equimolar amounts of the reacting       carboxylic acid and hydroxyl compound are employed. Although the present     invention is of general value for the preparation of esters, its main area     of application will therefore be in the synthesis of esters of expensive     starting materials, where the use of large excess of one reactant is     highly uneconomical.

Steroid alcohols esterified with valuable carboxylic acids are one suchtype of esters which are preferably synthesized by the method of thepresent invention. This class of esters is of great pharmaceuticalinterest, e.g. as anticancer agents (14, 16) and as long-acting hormonalagents (15). Several steroid esters of carboxylic acids have now beenprepared by pyridine using DCC as condensing agent. The catalytic effectof pTSA on the reactions is evident from the yields given in Table 2.

Other types of esters of great pharmaceutical interest which areprepared from expensive starting materials, and which may convenientlybe synthesized by the method of the present invention, are for instanceesters of penicillins, cephalosporins, prostaglandins, neuroleptics, andcertain amino acids.

In the esterifications mentioned above, pTSA and DCC may be replaced byother strong acids and carbodiimides, respectively. Thus, the promotingeffect on the formation of ester exerted by an acid catalyst in thepresence of pyridine seems to be a general phenomenon when carbodiimidesare used as condensing agents.

SUMMARY OF THE INVENTION

The object of the invention is to provide a process for the preparationof carboxylic esters of high purity and at an improved yield. Theprocess comprises reacting in solution a carboxylic acid, a hydroxylcompound, and a carbodiimide in the presence of pyridine, or pyridinesubstituted in 3- or 4-position with a lower alkyl group, and a strongacid which can be present in a catalytic amount, the improvement beingcharacterized by the use of said strong acid.

Carboxylic acids suitable to be transferred to their carboxylic acidesters by using the method of the present invention may have verydifferent structures but are in general expensive to buy or prepare. Ifsuch acids have substituents which may react with the carboxylic acidpart of the molecule during the reaction conditions employed, e.g.reactive hydroxy-, amino-, or thiol-groups, such groups are protected bymethods known per se during the reaction (see for example ref. 17).

Among carboxylic acids of interest the following general types may bementioned: substituted benzoic acids, substituted arylalkanoic acids,e.g. substituted phenylalkanoic acids, and saturated or unsaturated,straight or branched alkanoic acids, optionally substituted, and havingat most 22 carbon atoms, e.g. decanoic acid, undecylenic acid,arachidonic acid, behenic acid, and 2-ketobutyric acid.

Other types of carboxylic acids are such as: substituted orunsubstituted prostanoic acids and its homologs, e.g. the natural orsynthetic prostaglandins; N-derivatives of 6-aminopenicillanic acid and7-aminocephalosporanic acid such as benzylpenicillin,phenoxymethylpenicillin, dicloxacillin, cephalothin, and cephapirin;amino acids; peptides; different kinds of glucuronides, ethacrynic acid,dehydrocholic acid, 1-adamantanecarboxylic acid, furosemide, andretinoic acid.

Preferred carboxylic acids are substituted benzoic acids and substitutedphenylalkanoic acids, both types having at most 22 carbon atoms and ineither case having a bis β- or α-haloalkyl substituted amino group or analkoxy group having preferably three to twelve carbon atoms, as onesubstituent in the benzene ring. Especially preferred acids of thesetypes are: 3-(bis-(2-chloroethyl) amino)-4-methylbenzoic acid,4-(bis-(2-chloroethyl)amino)phenylacetic acid, 3-(4-bis-(2-chloroethyl)aminophenyl)-2-aminopropionic acid,3-(4-bis-(2-chloroethyl)aminophenyl)-2-acetamidopropionic acid,4-(4-bis-(2-chloroethyl)aminophenyl)butyric acid, and 3-(4-alkoxyphenyl)propionic acids such as 3-(4-propyloxyphenyl)propionic acid and3-(4-hexyloxyphenyl) propionic acid.

Hydroxy group containing compounds suitable to be esterified bycarboxylic acids using the method of the present invention may have verydifferent structures but are in general expensive to buy or prepare. Itis preferred that hydroxyl groups which are to be esterified areprimarily, secondary, or phenolic. If the hydroxy compounds haveadditional substituents which may react, during the reaction conditionemployed, such substituents, such as carboxylic acid groups, hydroxygroups, thiol groups, or amino groups, are protected by methods knownper se during the reaction (see for example ref. 17 and 18).

Among suitable compounds containing hydroxy groups the following generaltypes may be mentioned: natural or synthetic steroids having acyclopentanophenanthrene carbon-carbon skeleton or its homologs andcontaining up to a maximum of 40 carbon atoms and having at least oneprimary, secondary, or phenolic hydroxy group as a substituent;saturated or unsaturated alkanols, optionally substituted; e.g.2-octanol, 9-decen-1-ol, and 1-octyn-3-ol; tetracyclines; neuroleptics,e.g. flupenthixol, acephenazin, and clopenthixol.

Other types of hydroxy compounds are such as: morphine, nalorphine,oxyphenylbutazone, vitamins A and D, erythromycin, chloramphenicol,atropine, podophyllotoxin, yohimbine, adamantanols, cytochalosin B,quinidine, and 4-(bis(2-chloroethyl)amino)phenol.

Preferred hydroxy group containing compounds are steroids having acarbon-carbon skeleton selected from the group consisting of:estra-1,3,5(10)-triene, androstane, androst-4-ene, androst-5-ene,estr-4-ene, estr-5(10)-ene, pregn-4-ene, pregna-4,6-diene, pregn-5-ene,pregna-1,4-diene, cholestane, and cholest-5-ene.

It is preferred that the hydroxy group or groups which are to beesterified are situated in the 3-, 16-, 17-, or 21-positions of the saidcarbon-carbon skeletons. Their 17- and 21-positions are especiallypreferred when the hydroxy group to be esterified is a secondary one ora primary one, respectively.

Preferred steroids have a nucleus selected from the group consisting of:estra-1,3,5(10)-trien-3-ol-17-ones,estra-1,3,5(10)-triene-3,16-diol-17-ones,estra-1,3,5(10)-triene-3,16,17-triols,estra-1,3,5(10)-triene-3,17-diols, androstan-3-ol-17-ones,androstan-17-ol-3-ones, androstane-3,17-diols,androst-4-en-17-ol-3-ones, androst-4-ene-3,17-diols,androst-5-en-3-ol-17-ones, androst-5-en-17-ol-3-ones,androst-5-ene-3,17-diols, estr-4-en-17-ol-3-ones, estr-4-ene-3,17-diols,pregna-4-en-21-ol-3,20-diones, pregn-4-ene-11,21-diol-3,20-diones,pregn-4-ene-21-ol-3,11,20-triones,pregn-4-ene-17,21-diol-3,11,20-triones,pregn-4-ene-11,17,21-triol-3,20-diones,pregn-4-ene-11,16,17,21-tetraol-3,20-diones,pregna-1,4-diene-17,21-diol-3,11,20-triones,pregna-1,4-diene-11,17,21-triol-3,20-diones,pregna-1,4-diene-11,16,17,21-tetraol-3,20-diones, cholestan-3-ols, andcholest-5-en-3-ols wherein any further substitution in the carbon-carbonskeleton of said steroid nucleus is at most a tri-substitution whereinthe positions of the steroid carbon-carbon skeleton which aresubstituted are selected from the positions consisting of the 6-, 9-,17-, and 18-positions; where the substitution, if any, comprises atleast one substituent selected from the group consisting of methyl,ethynyl, fluoro, and chloro.

Hydroxy groups present in said steroid nucleus and which are not to beesterified by the present method may be free, esterified with amonocarboxylic acid selected from the group consisting of lower alkanoicacids and benzoic acid, etherified with an alcohol selected from thegroup consisting of aliphatic or alicyclic alcohols having at most 6carbon atoms, or transformed to an acetonide.

As examples of steroids and derivatives thereof which can be used ashydroxyl compounds in the present method the following may be mentionedusing the trivial names of the steroid as found in the literature (e.g.in the ninth edition of the Merck Index):

estrone; estradiol; estradiol 3-acetate; estradiol 17β-acetate; estriol3-acetate; estriol 3,16α-diacetate; estriol 16α,17β-diacetate; estradiol3-methylether; estradiol 3-cyclopentylether; 17α-ethynylestradiol;androsterone; epiandrosterone; dihydrotestosterone; androstanediol;androstanediol 3α-acetate; testosterone; androstenediol; androstenediol3β-acetate; dehydroepiandrosterone; 19-nortestosterone; ethynodiol;pregnenolone; desoxycorticosterone; cortisone; hydrocortisone;prednisone; prednisolone; prednisolone 17-benzoate;9α-fluoro-16α-methylprednisolone; 9α-fluoro-16β-methylprednisolone;9α-fluoro-16α-hydroxyprednisolone, 16,17-acetonide; and cholesterol.

Especially preferred steroids are testosterone, dihydrotestosterone,19-nortestosterone, deoxycorticosterone, cortisone, hydrocortisone,prednisone, and prednisolone.

Most preferred are 19-nortestosterone and prednisolone.

Various types of carbodiimides may be employed such as N,N¹ -aliphatic,e.g. N,N¹ -dicyclohexylcarbodiimide and N,N¹ -diisopropylcarbodiimide,or N,N¹ -aromatic, e.g. N,N¹ -di-p-tolylcarbodiimide.

The preferred carbodiimide is N,N¹ -dicyclohexylcarbodiimide.

The strong acid may be an organic or an inorganic acid, such as asulfonic acid, e.g. p-toluenesulfonic acid or methanesulfonic acid,sulfuric acid, nitric acid, perchloric acid, or a hydrogen halide, e.g.hydrogen chloride, hydrogen bromide, or hydrogen iodide. According tousual definition, as recognized in the chemical art, such strong acidhas a thermodynamic dissociation constant K in water at 25° C. greaterthan one (K being defined in ref. 19). Examples of dissociationconstants for some of these acids are as follows: nitric acid has a K of23 and methanesulfonic acid has a K of about 4 (see ref. 22).

The sulfonic acids are preferred.

The strong acid may be used in a catalytic amount, preferably in therange of 0.02 to 0.10 mole per mole of limiting reactant as largeamounts may lead to side-reactions. In this disclosure the limitingreactant means the least abundant ester forming component calculated ona molar basis.

The solvent employed may be any conventional solvent, well known in theart for esterification reactions, or mixture of such solvents compatiblewith the reaction. Such solvent may be hydrocarbons, halogenatedhydrocarbons, ethers, esters or ketones.

Among the halogenated and non-halogenated hydrocarbons the following maybe mentioned as representative solvents: chloroform, dichloromethane,benzene, chlorobenzene, and toluene.

It is preferred that the ethers, esters, and ketones are aliphatic.Representative examples of such solvents are dioxane, tetrahydrofurane,diethyl ether, ethyl acetate, and acetone.

As indicated above, the presence of pyridine, or pyridine substituted in3- or 4-position with a lower alkyl group, is essential to the reaction.The pyridine, or the above-mentioned pyridine derivative, is preferablyused in an amount at least equivalent to the limiting reactant and maybe used even as the sole solvent.

Whenever convenient, any of the reactants may be used as solvent.

Pyridine is the particularly preferred solvent.

REACTION TEMPERATURE

The reaction may be conducted conveniently at room temperature. Thereaction is frequently exothermic and can be controlled by a coolingprocess if desired.

The temperature is not critical except that it should not be so high asto produce undesirable side-effects, or so low that the reactionproceeds so slowly as to be at an uneconomic rate.

REACTION PRESSURE

The pressure used above the reaction mixture during the reaction is notparticularly critical. For most purposes atmospheric pressure isadequate. In some cases, however, superatmospheric pressure may bedesired and is serviceable. The pressure may also be below atmosphericpressure, if desired.

REACTION TIME

The reaction period may vary widely but for best yields and greatesteconomy the reaction must be allowed sufficient time to go tocompletion. Usually, at room temperature, 24 hours reaction time issufficient.

MOLAR RATIOS

The ester forming components, namely the alcohol and the carboxylic acidare generally employed in approximately equivalent amounts, However,excess of one reactant does not give rise to any detrimental effectswhatever upon the reaction except loss of economy and the usuallyattendant problems of incompletely reacted starting materials. Whenesters of lower alkanols are being made, the alkanols are sometimesemployed as cosolvent in the reaction, and the excess is subsequentlyremoved by distillation.

A slight molar excess of carbodiimide over the molar amount of thecarboxylic groups is usually employed. Unreacted carbodiimide maysubsequently be destroyed by the addition of a lower alkanoic acid, e.g.acetic acid.

WORK-UP PROCEDURE

The reaction mixture containing the desired product is worked upaccording to normal procedures, as apparent to those skilled in the art.

In this disclosure the expression "lower" means that the group referredto contains one to four carbon atoms, inclusive. Thus, lower alkyl,lower alkanol, and lower alkanoic include: methyl, ethyl, propyl,isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, methanol,ethanol, propanol, isopropanol, butanol, isobutanol, secondary butanol,tertiary butanol, methanoic, ethanoic, propanoic, butanoic, andisobutanoic.

The nomenclature used in this disclosure is in accordance with the rulesissued by the IUPAC Commission on the Nomenclature of Organic Chemistry,1957, 1965, and 1971.

The following examples are intended to illustrate but not to limit thescope of the invention, although the reagents named and the estersobtained are of particular interest for our intended purposes.

EXAMPLE 1

pTSA (0.100 g) is added to a mixture of benzoic acid (12.2 g) and1-hexanol (11.2 g) in pyridine (30 ml). To the homogenous solution DCC(24.8 g) is added, and the solution is stirred at room temperature for24 h. After addition of acetic acid (10 ml) the solution is keptovernight at +4° C. and then filtered. The crystals are washed with coldpyridine, and to the filtrate chloroform (100 ml) and ice (100 g) areadded. The stirred mixture is acidified with 5 M HCl, and phases areseparated, and the organic phase washed with water, aq. NaHCO₃, andwater, dried and evaporated to give hexyl benzoate (95% yield) b. p.99°-100° C. (0.10 mm Hg) [lit. (10), 101° C. (0.10 mm Hg)].

When the above reaction is carried out in the absence of pTSA, the yieldof ester is reduced to 40%.

When 1-hexanol is replaced by equimolar amounts of isopropanol in theabove reaction, the yield of isopropyl benzoate is 98% when the reactionis carried out in the presence of pTSA and 5% when the reaction isperformed in the absence of pTSA. B. p. of isopropyl benzoate: 104°-105°C. (20 mm Hg) [lit. (11), 106.5°-107.5° C. (21 mm Hg)].

When 1-hexanol is replaced by equimolar amounts of tert. butanol in theabove reaction, tert. butyl benzoate is obtained in 8% yield afterchromatography of the reaction product on a silica gel column if thereaction is carried out in the presence of pTSA. If pTSA is omitted, notert. butyl benzoate is obtained from the reaction mixture. B. p. oftert. butyl benzoate: 94°-95° C. (10 mm Hg) [lit. (11), 91.3° C. (7.5 mmHg)].

When 1-hexanol is replaced by equimolar amounts of phenol in the abovereaction, phenyl benzoate is obtained in a 96% yield if the reaction iscarried out in the presence of pTSA and in a 20% yield if the reactionis performed in the absence of pTSA. M. p. of phenyl benzoate afterrecrystallization from petroleum ether: 69°-70° C. (lit. (7), 70°-71°C.).

EXAMPLE 2

To a mixture of 3-phenylpropionic acid (15.0 g) and 1-butanol (8.15 g)in pyridine (30 ml) pTSA (0.100 g) is added. When the solution ishomogeneous, DCC (24.8 g) is added, and the solution is stirred at roomtemperature for 24 h. After addition of acetic acid (10 ml) the reactionmixture is worked up as in Example 1. A 96% yield of butyl3-phenylpropionate is obtained, b. p. 112°-3° C. (1 mm Hg) [lit. (12),91° C. (0.3 mm Hg)].

When pTSA is omitted from the above reaction mixture the yield of esteris reduced to 66%.

Substituting N,N¹ -diisopropylcarbodiimide, N-(3-dimethylaminopropyl)-N¹-ethylcarbodiimide, or N,N¹ -di-p-tolylcarbodiimide for DCC in the abovereaction leads to yields of 93, 88, and 90%, respectively, in thepresence of pTSA, and to yields of 58, 69, and 66%, respectively, in theabsence of pTSA.

Replacing 1-butanol by equimolar amounts of isopropanol in the firstreaction in this example gives a 99% yield of isopropyl3-phenylpropionate if the reaction is carried out in the presence ofpTSA and a 58% yield of said ester if the reaction is performed in theabsence of pTSA. B. p. of isopropyl 3-phenylpropionate: 92°-3° C. (1 mmHg) [lit. (12), 89° C. (0.9 mm Hg)].

Replacing 1-butanol by equimolar amounts of tert. butanol in the firstreaction in this example gives a 17% yield of tert. butyl3-phenylpropionate if the reaction is carried out in the presence ofpTSA and a 3% yield of said ester if the reaction is performed in theabsence of pTSA. B. p. of tert. butyl 3-phenylpropionate: 95°-6° C. (1mm Hg) [lit. (12), 84°-5° C. (0.5 mm Hg)].

When 1-butanol is replaced by equimolar amounts of phenol in the firstreaction in this example, phenyl 3-phenylpropionate is obtained in a 93%yield if the reaction is performed in the presence of pTSA and in a 39%yield if the reaction is carried out in the presence of pTSA. M. p. ofphenyl 3-phenylpropionate after distillation at reduced pressure andrecrystallization from light petroleum: 15°-16° C. (lit. (13), 16°-17°C.).

EXAMPLE 3

11β,17,21-trihydroxypregna-1,4-diene-3,20-dione (prednisolone, 7.20 g)and 4-[4-(N,N-bis(2-chloroethyl)amino)phenyl]butyric acid (chlorambucil,7.00 g) is dissolved in dry pyridine (60 ml). pTSA (0.200 g) is addedand the mixture is stirred for 15 min. To the homogeneous solution DCC(5.77 g) is added, and stirring is continued for 24 h at roomtemperature. Acetic acid (2 ml) is added, and the reaction mixture iskept overnight at +4° C. The solution is filtered and the crystals arewashed with cold pyridine. To the filtrate a mixture of ethyl acetate(100 ml), ether (100 ml), and ice (100 g) is added, and 5 M HCl is thenslowly added to the stirred solution until pH reaches 2.5. The organicphase is washed with water, 0.5 M aq. K₂ CO₃, and water. After removalof the solvent and recrystallization from isopropanol21-[4-(4-(N,N-bis(2-chloroethyl)amino)phenyl)butanoyloxy]-11β,17-dihydroxypregna-1,4-diene-3,20-dione (prednimustine), m. p. 165°-166° C., is obtained inan 85% yield.

The structure is confirmed by comparison with a sample prepared byanother route (14) and by physical data such as NMR, IR, and analysisfor Cl and N. The significant signals of the NMR spectrum (60 MHz,CDCl₃) are the following: δ(ppm) 0.95 (s, 3H, H-18), 1.44 (s, 3H, H-19),3.67 (s, 8H, --CH₂ CH₂ Cl), 4.50 (broad signal, 1H, H-11), 5.00 (s, 2H,--COCH₂ OCO--), 6.03 (d, 1H, H-4, J₄,2 =2 Hz), 6.30 (dd, 1H, H-2, J₂,1=10 Hz, J₂,4 =2 Hz), 6.69 and 7.12 (doublets, 2H each, aromatic H, J=8Hz), 7.33 (d, 1H, H-1, J₁,2 =10 Hz).

When the above reaction is carried out in the absence of pTSA the yieldof the steroid ester is reduced to 74%.

EXAMPLE 4

Using the same procedure as in Example 3, but replacing chlorambucilwith 3-[N,N-bis(2-chloroethyl)amino]-4-methylbenzoic acid, results in acrude product obtained after the evaporation of the ether/ethyl acetatecontaining <0.5% prednisolone and 2-3% of other impurities when pTSA ispresent during the reaction and >4% of prednisolone and >10% of otherimpurities when no pTSA is added to the reaction mixture. Afterrecrystallization from methanol/water the former product gives21-[3-(N,N-bis(2-chloroethyl)amino)-4-methylbenzoyloxy]-11α,17-dihydroxypregna-1,4-diene-3,20-dionein 89% yield with 0.1% prednisolone being the main impurity and havingthe m. p. 168° C., while the other crude product gives a product, m. p.145°-55° C., containing the mentioned compound in 73% yield and 15% ofprednisolone and other impurities.

The structure is confirmed by comparison with a sample prepared byanother route (14) and by physical data such as NMR, IR, and analysisfor Cl and N. The significant signals of the NMR spectrum (60 MHz,CDCl₃) are the following: δ(ppm) 0.98 (s, 3H, H-18), 1.44 (s, 3H, H-19),3.44 (s, 8H, --CH₂ CH₂ Cl), 4.50 (broad signal, 1H, H-11), 5.25 (s, 2H,--COCH₂ OCO--), 6.02 (d, 1H, H-4, J₄,2 =2 Hz), 6.28 (dd, 1H, H-2, J₂,1=10 Hz, J₂,4 =2 Hz), 7.26 and 7.76 (doublets with J=8 Hz, 1H each,aromatic H), 7.33 (d, 1H, H-1, J₁,2 =10 Hz), 7.85 (s, 1H, aromatic H).

When the above reaction is performed without pTSA the yield of thesteroid ester is 73%.

EXAMPLE 5

To a solution of 17β-hydroxyestr-4-en-3-one (5.48 g) and3-(4-hexyloxyphenyl)propionic acid (5.75 g) in dry pyridine (60 ml) pTSA(0.200 g) and DCC (5.77 g) are added. After 72 h stirring at roomtemperature acetic acid (2 ml) is added, and the reaction mixture iskept overnight at +4° C. The same work-up procedure as in Example 1gives 17β-[3-(4-hexyloxyphenyl)-propanoyloxy]estr-4-en-3-one (m. p.52°-53° C.) in a 87% yield after recrystallization from methanol/water.

The structure is confirmed by comparison with a sample prepared byanother route (15) and by physical data such as NMR, IR, and UV. Thesignificant signals of the NMR spectrum (60 MHz, CDCl₃) are thefollowing: δ(ppm), 0.80 (s, 3H, H-18), 3.93 (t, 2H, φ-O-CH₂ -), 4.65 (t,1H, H-17), 5.85 (s, 1H, H-4), 6.83 and 7.11 (doublets, 2H, each,aromatic H, J=9 Hz).

When the above reaction is carried out in the absence of pTSA the yieldof the steroid ester is reduced to 50%.

EXAMPLE 6

pTSA (0.100 g) is added to a mixture of benzoic acid (12.2 g) andisopropanol (6.61 g) in ethyl acetate-pyridine 9:1 (100 ml). After 15min. stirring, DCC (24.8 g) is added and stirring is continued at roomtemperature for 24 h. Acetid acid (10 ml) is added, and the reactionmixture is worked-up as described in Example 1 to give isopropylbenzoate (b. p., see Example 1) in a 97% yield.

The ethyl acetate-pyridine mixture used as solvent in the above reactionmay be replaced by other combinations of solvents, e.g.tetrahydrofuran-pyridine or abs. chloroform-pyridine in proportionsbetween 1:9 and 9:1 without any substantial change in yield. When4-methylpyridine is used as solvent in the above reaction the yield ofisopropyl benzoate is 81%.

When the above reaction is performed in the absence of pTSA in any ofthe solvents mentioned above, the yield of isopropyl benzoate is reducedto below 40%.

EXAMPLE 7

To a mixture of 3-phenylpropionic acid (15.0 g) and isopropanol (6.61 g)in pyridine (30 ml) perchloric acid (0.150 g) and DCC (24.8 g) areadded. After stirring at room temperature for 24 h acetic acid (10 ml)is added, and the reaction mixture is worked-up as described in Example1 to give a 94% yield of isopropyl 3-phenylpropionate (b. p., seeExample 2).

Perchloric acid may be replaced as catalyst in the above reaction byequimolar amounts of other strong acids, e.g. methanesulfonic acid,hydrogen chloride, nitric acid, hydrogen bromide,trifluoromethanesulfonic acid, hydrogen iodide, benzenesulfonic acid, orsulfuric acid, without any substantial change in yield.

If the above reaction is carried out in the absence of an acid catalystthe yield of isopropyl 3-phenylpropionate is 58%.

EXAMPLE 8

Using essentially the same reaction conditions as described in Example 3esters were prepared from the alcohols and acids mentioned below withDCC as condensing agent and pyridine as solvent. The yields were in eachcase substantially higher when pTSA was used as a catalyst than when nostrong acid was present in the reaction mixture. The following esterswere made:

3-ester of estrone with acetic acid (20);

p-p¹ -diester of diethylstilbestrol with propionic acid (20);

21-ester of dexamethasone with heptanoic acid (20);

21-ester of prednisone with 4-(bis(2-chloroethyl)amino)benzoic acid(14);

17β-ester of 19-nortestosterone with 3-phenylpropionic acid (20) anddecanoic acid (20);

3-esters of 5-cholesten-3-ol and of 24-ethyl-5-cholesten-3-ol with4-(bis(2-chloroethyl)amino)phenylacetic acid (21, 20);

17β-ester of 17β-hydroxy-1,4-androstadien-3-one with 10-undecenoic acid(20);

3,17β-diester of estradiol with 3-(4-(propyloxy)phenyl)propionic acid(15);

21-ester of 9α-fluoroprednisolone with acetic acid (20); 21-ester ofhydrocortisone with 3-cyclopentylpropionic acid (20) and4-(bis(2-chloroethyl)amino)phenylacetic acid (14);

17β-ester of testosterone with 3-(4-(butyloxy)phenyl)propionic acid(15), propionic acid (20), heptanoic acid (20);

21-ester of prednisolone with 3-(bis(2-chloroethyl)amino)phenylaceticacid (14), 4-(bis(2-chloroethyl)amino)phenylacetic acid (14),2-acetamido-3-(4-bis(2-chloroethyl)amino)phenyl)propionic acid (14);

17β-ester of 17β-hydroxy-1-methyl-5α-androst-1-en-3-one with heptanoicacid (20);

21-ester of cortisone with 4-(bis(2-chloroethyl)amino)benzoic acid (14).

It is to be understood that the invention is not limited to the exactdetails of operation or exact compounds shown or described, as obviousmodifications and equivalents will be apparent to one skilled in theart.

REFERENCES

1. Kurzer, F. and Douraghi-Zadeh, K. Chem. Rev. 67 (1967) 107.

2. Felder, E., Tiepolo, U., and Mengassini, A. J. Chromatogr. 82 (1973)291.

3. Fieser, L. F. and Fieser, M. Reagents for Organic Synthesis, Wiley,New York 1967.

4. Zetzsche, F. and Fredrich, A. Ber. Deut. Chem. Ges. 72 (1939) 1735.

5. Vowinkel, E. Chem. Ber. 100 (1967) 16.

6. Henecka, H. in Muller, E. (Ed.) Methoden der organischen Chemie(Houben-Weyl), Band VIII (1952) 521.

7. Neelakantan, S., Padmasani, R., and Seshadri, T. R. Tetrahedon 21(1965) 3531.

8. Fersht, A. R. and Jencks, W. P. J. Amer. Chem. Soc. 91 (1969) 2125.

9. Knoblich, J. M., Sugihara, J. M., and Yamazaki, T. J. Org. Chem. 36(1971) 3407.

10. Hoffman, F. W. and Weiss, H. D. J. Amer. Chem. Soc. 79 (1957) 4759.

11. Cohen, S. G. J. Amer. Chem. Soc. 66 (1944) 1395.

12. Takahashi, S., Cohen, L. A., Miller, H. K., and Peake, E. G. J. Org.Chem. 36 (1971) 1205.

13. Poulsen, E. and Aldridge, W. N. Biochem. J. 90 (1964) 182.

14. Fex, H. J., Hogberg, K. B., and Konyves, I. U.S. Pat. 3,732,260(1973).

15. Diczfalusy, E., Ferno, O., Fex, H., and Hogberg, B, Acta Chem.Scand. 17 (1963) 2536.

16. Konyves, I. and Liljekvist, J. (1975): In: Proceedings of the SixthInternational Symposium on the Biological Characterization of HumanTumors, p. 98. Excerpta Medica, Amsterdam.

17. McOmie, J. F. W. Protective Groups in Organic Chemistry, PlenumPress, London 1973.

18. Djerassi, C. Steroid Reactions, Holden-day, San Francisco 1963,chapter 1.

19. Bell, R. P. The Proton in Chemistry, 2nd Ed., Chapman and Hall,London 1973, p. 26-28.

20. Negwer, M. Organisch-Chemische Arzeimittel and ihre Synonyma,Akademie-Verlag, Berlin, 1971.

21. Wall, M. E., Abernethy, Jr., G. S., Carrol, F. I. and Taylor, D. J.J. Med. Chem. 12 (1969) 810.

22. Bascombe, K. N. and Bell, R. P. J. Chem. Soc. (1959) 1104.

We claim:
 1. In a process for the preparation of a steroid carboxylicacid ester of high purity and in improved yield, comprising reacting insolution a carboxylic acid, a steroid hydroxyl compound which has acyclopentanophenanthrene carbon-carbon skeleton and contains up to amaximum of 40 carbon atoms and which is selected from the groupconsisting of steroid alcohols and phenols, and a carbodiimide, in thepresence of pyridine or a 3- or 4- lower-alkylpyridine, the improvementwhich comprises the step of including in the reaction mixture a strongacid.
 2. The process of claim 1, wherein the strong acid is employed ina catalytic amount.
 3. The process of claim 2, wherein the amount ofstrong acid is in the range of 0.02 to 0.10 mole per mole of thelimiting ester-forming component.
 4. The process of claim 2, wherein thestrong acid is sulfuric acid, nitric acid, perchloric acid, a sulfonicacid, or a hydrogen halide.
 5. The process of claim 4, wherein thesulfonic acid is p-toluensulfonic acid or methane sulfonic acid.
 6. Theprocess of claim 4, wherein the hydrogen halide is hydrogen chloride,hydrogen bromide, or hydrogen iodide.
 7. The process of claim 1, whereinthe pyridine or lower-alkylpyridine is present in an amount at leastequivalent to the limiting esterforming component.
 8. The process ofclaim 7, wherein pyridine is employed.
 9. The process of claim 1,wherein the carbodiimide is present in a molar amount at leastequivalent to the molar amount of carboxylic groups.
 10. The process ofclaim 9, wherein the carbodiimide is an N,N¹ -dialiphatic or N,N¹-di-aromatic carbodiimide.
 11. The process of claim 10, wherein thecarbodiimide is N,N¹ -dicyclohexylcarbodiimide.
 12. The process of claim1, wherein the reaction is performed in an inert solvent or a mixture ofsuch solvents.
 13. The process of claim 12, wherein the solent isselected from the group consisting of hydrocarbons, halogenatedhydrocarbons, ethers, esters, and ketones.
 14. The process of claim 13,wherein the solvent is selected from aliphatic ethers, esters, andketones.
 15. The process of claim 13, wherein the solvent is selectedfrom chloroform, dichloromethane, benzene, chlorobenzene, and toluene.16. The process of claim 14, wherein the solvent is selected fromdioxane, tetrahydrofurane, diethylether, ethylacetate, and acetone. 17.The process of claim 1, wherein the reaction is performed at roomtemperature.
 18. The process of claim 1, wherein the carboxylic acid andthe hydroxyl compound are present in approximately equivalent amounts.19. The process of claim 1, wherein the steroid hydroxyl compound isselected from the group consisting of primary and secondary alcohols andphenols.
 20. The process of claim 1, wherein the carboxylic acid is acarboxylic acid having at most 22 carbon atoms, selected from the groupconsisting of aliphatic acids and phenylalkanoic acids.
 21. The processof claim 1, wherein the carboxylic acid is a phenylalkanoic acid havinga ring bis(β- or α-haloalkyl)amino group.
 22. The process of claim 21,wherein said steroid contains at least one free hydroxy group in the 3-,16-, 17-, or 21-positions, said positions being identified according tosteroid nomenclature.
 23. The process of claim 22, wherein thecarboxylic acid is a phenylalkanoic acid having a ring bis(β- orα-haloalkyl)amino group.
 24. The process of claim 1, wherein the strongacid has a thermodynamic dissociation constant K in water greater thanone.
 25. The process of claim 23, wherein said steroid hydroxyl compoundis 19-nortestosterone or prednisolone.